Familial Immune Thrombocytopenia Associated With a Novel Variant in IKZF1

Abstract

We report a novel variant in <i>IKZF1</i> associated with IKAROS haploinsufficiency in a patient with familial immune thrombocytopenia (ITP). IKAROS, encoded by the <i>IKZF1</i> gene, is a hematopoietic zinc-finger transcription factor that can directly bind to DNA. We show that the identified <i>IKZF1</i> variant (p.His195Arg) alters a completely conserved histidine residue required for the folding of the third zinc-finger of IKAROS protein, leading to a loss of characteristic immunofluorescence nuclear staining pattern. In our case, genetic testing was essential for the diagnosis of IKAROS haploinsufficiency, of which known presentations include infections, aberrant hematopoiesis, leukemia, and age-related decrease in humoral immunity. Our family study underscores that, after infections, ITP is the second most common clinical manifestation of IKAROS haploinsufficiency.